In this chapter the application of nuclear magnetic resonance (NMR) spectroscopy to the study of ... more In this chapter the application of nuclear magnetic resonance (NMR) spectroscopy to the study of cancer will be discussed. As cancer continues to be a leading cause of death and primary focus of physicians, biomedical researchers, and health care adminstrators throughout the world, interest remains high in the utilization of diagnostic technologies that provide unique capabilities for the detection and management of this disease. In vivo NMR spectroscopy is one of the most promising of the new diagnostic methods. This technique holds considerable promise for diagnosis and staging of cancer, for prediction and detection of therapeutic response, for monitoring pharmacokinetics of antineoplastic agents, and for detection of toxicity of anticancer agents to vital normal tissues. In addition to these potential clinical capabilities, NMR spectroscopy has already demonstrated its utility in experimental investigations of the biochemical and physiological characteristics of cancer.
Primary Amide Hydrogen Exchange in Model Amino Acids: ... N. Rama Krishna,*lPvb K. Partha Sarathy... more Primary Amide Hydrogen Exchange in Model Amino Acids: ... N. Rama Krishna,*lPvb K. Partha Sarathy,' Dee-Hua Huang,ln,c Richard L. Stephens,lP,d Jerry D. Glickson,' Clark W. Smith,leVf and Roderich Walterle>g ... Contribution from the Comprehensive Cancer Center, ...
A network model for determination of tumor metabolic fluxes from 13C NMR kinetic isotopomer data ... more A network model for determination of tumor metabolic fluxes from 13C NMR kinetic isotopomer data has been developed and validated with perfused human DB-1 melanoma cells carrying the BRAF V600E mutation, which promotes oxidative metabolism. The model generated in the Bonded Cumomer formalism describes key pathways of tumor intermediary metabolism and yields dynamic curves for positional isotopic enrichment and spin-spin multiplets. Cells attached to microcarrier beads were perfused with 26 mM [1,6-13C2]glucose under normoxic conditions at 37oC and monitored by 13C NMR spectroscopy. Excellent agreement between model-predicted and experimentally measured values of the rates of oxygen and glucose consumption, lactate production and glutamate pool size validated the model. ATP productions by glycolytic and oxidative metabolism were compared under hyperglycemic normoxic conditions resulting in 51% of the energy coming from oxidative phosphorylation and 49% from glycolysis. Even though th...
The goal of this study was to evaluate the utility of T1ρ weighting in magnetic resonance imaging... more The goal of this study was to evaluate the utility of T1ρ weighting in magnetic resonance imaging of murine brain tumors.S91 Cloudman melanoma was implanted in mouse brains (n = 4). A T2-weighted spin-echo (SE) and a T1ρ-weighted fast SE-based sequence were performed on a 4-T clinical imager. T2 and T1ρ maps were computed. The tumor-to-normal-tissue contrast was compared between T2-weighted, T1ρ-weighted, proton-density–weighted, and pre- and postcontrast T1-weighted SE images.The tumor-tissue contrast of the T1ρ-weighted images was similar to that of the T2-weighted images but less than that of the postcontrast T1-weighted images. The T1ρ-weighted images provided better definition of tumor boundaries than T2-weighted images. At spin-locking powers of 0.5 and 1.5 kHz, the T1ρ of the tumor was 64.0 msec ± 0.46 and 68.65 msec ± 0.59, respectively. There was no significant inter- or intra-animal variation in T1ρ for tumor or normal brain cortex.T1ρ-weighted imaging performed at low spin-lock strengths qualitatively depicted tumor borders better than proton-density or T2-weighted imaging and could be useful in treatment planning when combined with other imaging sequences.
Proceedings of The National Academy of Sciences, 2005
We report that a lipoprotein-based nanoplatform generated by conjugating tumor-homing molecules t... more We report that a lipoprotein-based nanoplatform generated by conjugating tumor-homing molecules to the protein components of naturally occurring lipoproteins reroutes them from their normal lipoprotein receptors to other selected cancer-associated receptors. Multiple copies of these targeting moieties may be attached to the same nanoparticle, or a variety of different targeting moieties can be attached. Such a diverse set of tumor-homing
In the present studies, the regulatory role of adrenal hormones on the antitumor activity of reco... more In the present studies, the regulatory role of adrenal hormones on the antitumor activity of recombinant human interleukin la (IL-la) was investigated. Ketoconazole, a potent but transient inhibitor of adrenal steroid hormone biosynthesis, inhibited IL-la induced increases in plasma corticosterone. In s.c. RIF-1 tumors (C3H/HeJ mice) ketocona- zole potentiated IL-la induced hemorrhagic necrosis ("Fe labeled RBC uptake) and prolonged intervals
An extension of the Sel-MQC pulse sequence--SEE-SelMQC (spin-echo-enhanced selective multiple-qua... more An extension of the Sel-MQC pulse sequence--SEE-SelMQC (spin-echo-enhanced selective multiple-quantum coherence transfer)--that completely suppresses lipid and water in tissues containing mobile lipid in a single scan and detects 1H resonances of multiple metabolites is described. As in the Sel-MQC lactate-editing experiments [Q. He et al., J Magn. Reson. B 106,203 (1995)], SEE-SelMQC acquires lactate from its ZQ --> DQ coherence-transfer pathway; in addition, the method recovers signal from other metabolites by selective generation of additional spin echoes using extra frequency-selective pulses and gradients. This method introduces no loss of lactate signal intensity beyond the 50% that is lost through the multiple-quantum coherence-transfer process. The spatial distributions of choline and lactate with a phantom and in vivo, in subcutaneously implanted murine EMT6 tumors, have been simultaneously mapped.
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 2004
A noninvasive technique for simultaneous measurement of the arterial input function (AIF) for gad... more A noninvasive technique for simultaneous measurement of the arterial input function (AIF) for gadodiamide (Omniscan) and its uptake in tumor was demonstrated in mice. Implantation of a tumor at a suitable location enabled its visualization in a cardiac short axis image. Sets of gated, low-resolution saturation recovery images were acquired from each of five tumor-bearing mice following intravenous administration of a bolus of contrast agent (CA). The AIF was extracted from the signal intensity changes in left ventricular blood using literature values of the CA relaxivity and a precontrast T1 map. The time-dependent 1H2O relaxation rate constant (R1 = 1/T1) in the tumor was modeled using the BOLus Enhanced Relaxation Overview (BOLERO) method in two modes regarding the equilibrium transcytolemmal water exchange system: 1) constraining it exclusively to the fast exchange limit (FXL) (the conventional assumption), and 2) allowing its transient departure from FXL and access to the fast e...
The aim of this study was to evaluate the ability of noninvasive 1H magnetic resonance spectrosco... more The aim of this study was to evaluate the ability of noninvasive 1H magnetic resonance spectroscopic imaging to detect the response of radiation-induced fibrosarcoma 1 tumors to treatment with 5-fluorouracil (5-FU). Parallel magnetic resonance studies of tumor extracts and assays of apoptosis and necrosis in tumor sections were performed to elucidate the mechanism underlying the changes detected in spectra in vivo. Cell death in tumors after a single dose of 5-FU (165 mg/kg, i.p.) was characterized by increased apoptosis, decreased necrotic fraction, and tumor shrinkage within 48 h. No significant change in normalized trimethylamine and lactate levels was observed during 3 days of untreated tumor growth. Following treatment with 5-FU, normalized intensities of both trimethylamine and lactate decreased significantly from pretreatment levels within 24 h and continued to decline at 48 h. The decrease in lactate levels determined by spectroscopic imaging in vivo was also observed in per...
In vivo nuclear magnetic resonance (NMR) spectroscopy is a rapidly developing, noninvasive analyt... more In vivo nuclear magnetic resonance (NMR) spectroscopy is a rapidly developing, noninvasive analytical technique that allows sequential studies of brain tumor metabolism. It can be implemented on most conventional high-field magnetic resonance imaging scanners. In animal tumor models, NMR spectroscopy has been used extensively to characterize the metabolic changes associated with tumor growth and response to therapy. Preliminary data in humans indicate the feasibility of recording phosphorus and proton spectra from focal lesions within the brain. It is hoped that the technique will provide useful prognostic information in terms of tumor growth behavior and prediction and detection of response to therapy. However, the technique suffers from relatively coarse spatial resolution, and the methodology is still under development. More studies with larger patient groups are required before the clinical utility of the technique can be fully evaluated.
A novel single-scan selective homonuclear multiple-quantum coherence-transfer technique, Sel-MQC,... more A novel single-scan selective homonuclear multiple-quantum coherence-transfer technique, Sel-MQC, is presented that achieves lactate editing with complete lipid and water suppression. The method is suitable for studying tissues with high fat content and those subject to substantial motion. Frequency-selective excitation is employed to selectively prepare lactate into its multiple-quantum states; lipid and water are left in the single-quantum modes and eliminated by the multiple-quantum selection gradients. The efficiency of lipid suppression is monitored by a 2D Sel-MQC experiment which separates lipid and lactate along the multiple-quantum-evolution dimension. The spatial distribution of lactate can be imaged by the spectroscopic imaging version of Sel-MQC. Sel-MQC sequences were demonstrated both in phantoms and in vivo, using subcutaneously implanted murine EMT6 tumors.
We have used in vivo 31P-nuclear magnetic resonance spectroscopy to study the changes in high-ene... more We have used in vivo 31P-nuclear magnetic resonance spectroscopy to study the changes in high-energy phosphates following hyperthermia. Immediately after heating, there is a fall in adenosine triphosphate and apparent intracellular pH and an increase in inorganic phosphate. Following sublethal heating (40 degrees for 15 min), these changes were partial, and they resolved over the subsequent 45 hr. With tumors given severe hyperthermia (47 degrees for 15 min), there was complete disappearance of adenosine triphosphate, with no recovery by 24 hr posttreatment. Qualitatively similar effects were seen after heating of normal leg muscle. The degree of fall of the adenosine triphosphate/inorganic phosphate concentration ratio was directly proportional to the heat dose and to thermal cell kill. 31P-Nuclear magnetic resonance spectroscopy may be useful in thermal dosimetry and treatment evaluation following hyperthermia.
If tumor volumes are to be used for evaluating responses to treatment and long-term outcomes of p... more If tumor volumes are to be used for evaluating responses to treatment and long-term outcomes of patients with primary pharyngeal carcinomas, the reproducibility of these measurements must be established. We determined the intraobserver variability of MR imaging-based volume measurements of these cancers and their regional metastases. We used an interactive computer program (IDL) that enables the extraction of tumor volumes from 3D MR data to obtain 202 volume measurements in 17 patients with pharyngeal carcinoma (two to five time points each). The primary cancer and largest nodal mass were manually outlined on every T2-weighted image of each MR study. The same neuroradiologist reanalyzed this MR dataset 2-41 weeks later. Measurement error and percentage measurement error (intraobserver variability) were determined. Differences in intraobserver variability between primary lesions and nodes, as well as between stages of treatment were tested with a Wilcoxon rank sum test. The mean and...
In this chapter the application of nuclear magnetic resonance (NMR) spectroscopy to the study of ... more In this chapter the application of nuclear magnetic resonance (NMR) spectroscopy to the study of cancer will be discussed. As cancer continues to be a leading cause of death and primary focus of physicians, biomedical researchers, and health care adminstrators throughout the world, interest remains high in the utilization of diagnostic technologies that provide unique capabilities for the detection and management of this disease. In vivo NMR spectroscopy is one of the most promising of the new diagnostic methods. This technique holds considerable promise for diagnosis and staging of cancer, for prediction and detection of therapeutic response, for monitoring pharmacokinetics of antineoplastic agents, and for detection of toxicity of anticancer agents to vital normal tissues. In addition to these potential clinical capabilities, NMR spectroscopy has already demonstrated its utility in experimental investigations of the biochemical and physiological characteristics of cancer.
Primary Amide Hydrogen Exchange in Model Amino Acids: ... N. Rama Krishna,*lPvb K. Partha Sarathy... more Primary Amide Hydrogen Exchange in Model Amino Acids: ... N. Rama Krishna,*lPvb K. Partha Sarathy,' Dee-Hua Huang,ln,c Richard L. Stephens,lP,d Jerry D. Glickson,' Clark W. Smith,leVf and Roderich Walterle>g ... Contribution from the Comprehensive Cancer Center, ...
A network model for determination of tumor metabolic fluxes from 13C NMR kinetic isotopomer data ... more A network model for determination of tumor metabolic fluxes from 13C NMR kinetic isotopomer data has been developed and validated with perfused human DB-1 melanoma cells carrying the BRAF V600E mutation, which promotes oxidative metabolism. The model generated in the Bonded Cumomer formalism describes key pathways of tumor intermediary metabolism and yields dynamic curves for positional isotopic enrichment and spin-spin multiplets. Cells attached to microcarrier beads were perfused with 26 mM [1,6-13C2]glucose under normoxic conditions at 37oC and monitored by 13C NMR spectroscopy. Excellent agreement between model-predicted and experimentally measured values of the rates of oxygen and glucose consumption, lactate production and glutamate pool size validated the model. ATP productions by glycolytic and oxidative metabolism were compared under hyperglycemic normoxic conditions resulting in 51% of the energy coming from oxidative phosphorylation and 49% from glycolysis. Even though th...
The goal of this study was to evaluate the utility of T1ρ weighting in magnetic resonance imaging... more The goal of this study was to evaluate the utility of T1ρ weighting in magnetic resonance imaging of murine brain tumors.S91 Cloudman melanoma was implanted in mouse brains (n = 4). A T2-weighted spin-echo (SE) and a T1ρ-weighted fast SE-based sequence were performed on a 4-T clinical imager. T2 and T1ρ maps were computed. The tumor-to-normal-tissue contrast was compared between T2-weighted, T1ρ-weighted, proton-density–weighted, and pre- and postcontrast T1-weighted SE images.The tumor-tissue contrast of the T1ρ-weighted images was similar to that of the T2-weighted images but less than that of the postcontrast T1-weighted images. The T1ρ-weighted images provided better definition of tumor boundaries than T2-weighted images. At spin-locking powers of 0.5 and 1.5 kHz, the T1ρ of the tumor was 64.0 msec ± 0.46 and 68.65 msec ± 0.59, respectively. There was no significant inter- or intra-animal variation in T1ρ for tumor or normal brain cortex.T1ρ-weighted imaging performed at low spin-lock strengths qualitatively depicted tumor borders better than proton-density or T2-weighted imaging and could be useful in treatment planning when combined with other imaging sequences.
Proceedings of The National Academy of Sciences, 2005
We report that a lipoprotein-based nanoplatform generated by conjugating tumor-homing molecules t... more We report that a lipoprotein-based nanoplatform generated by conjugating tumor-homing molecules to the protein components of naturally occurring lipoproteins reroutes them from their normal lipoprotein receptors to other selected cancer-associated receptors. Multiple copies of these targeting moieties may be attached to the same nanoparticle, or a variety of different targeting moieties can be attached. Such a diverse set of tumor-homing
In the present studies, the regulatory role of adrenal hormones on the antitumor activity of reco... more In the present studies, the regulatory role of adrenal hormones on the antitumor activity of recombinant human interleukin la (IL-la) was investigated. Ketoconazole, a potent but transient inhibitor of adrenal steroid hormone biosynthesis, inhibited IL-la induced increases in plasma corticosterone. In s.c. RIF-1 tumors (C3H/HeJ mice) ketocona- zole potentiated IL-la induced hemorrhagic necrosis ("Fe labeled RBC uptake) and prolonged intervals
An extension of the Sel-MQC pulse sequence--SEE-SelMQC (spin-echo-enhanced selective multiple-qua... more An extension of the Sel-MQC pulse sequence--SEE-SelMQC (spin-echo-enhanced selective multiple-quantum coherence transfer)--that completely suppresses lipid and water in tissues containing mobile lipid in a single scan and detects 1H resonances of multiple metabolites is described. As in the Sel-MQC lactate-editing experiments [Q. He et al., J Magn. Reson. B 106,203 (1995)], SEE-SelMQC acquires lactate from its ZQ --> DQ coherence-transfer pathway; in addition, the method recovers signal from other metabolites by selective generation of additional spin echoes using extra frequency-selective pulses and gradients. This method introduces no loss of lactate signal intensity beyond the 50% that is lost through the multiple-quantum coherence-transfer process. The spatial distributions of choline and lactate with a phantom and in vivo, in subcutaneously implanted murine EMT6 tumors, have been simultaneously mapped.
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 2004
A noninvasive technique for simultaneous measurement of the arterial input function (AIF) for gad... more A noninvasive technique for simultaneous measurement of the arterial input function (AIF) for gadodiamide (Omniscan) and its uptake in tumor was demonstrated in mice. Implantation of a tumor at a suitable location enabled its visualization in a cardiac short axis image. Sets of gated, low-resolution saturation recovery images were acquired from each of five tumor-bearing mice following intravenous administration of a bolus of contrast agent (CA). The AIF was extracted from the signal intensity changes in left ventricular blood using literature values of the CA relaxivity and a precontrast T1 map. The time-dependent 1H2O relaxation rate constant (R1 = 1/T1) in the tumor was modeled using the BOLus Enhanced Relaxation Overview (BOLERO) method in two modes regarding the equilibrium transcytolemmal water exchange system: 1) constraining it exclusively to the fast exchange limit (FXL) (the conventional assumption), and 2) allowing its transient departure from FXL and access to the fast e...
The aim of this study was to evaluate the ability of noninvasive 1H magnetic resonance spectrosco... more The aim of this study was to evaluate the ability of noninvasive 1H magnetic resonance spectroscopic imaging to detect the response of radiation-induced fibrosarcoma 1 tumors to treatment with 5-fluorouracil (5-FU). Parallel magnetic resonance studies of tumor extracts and assays of apoptosis and necrosis in tumor sections were performed to elucidate the mechanism underlying the changes detected in spectra in vivo. Cell death in tumors after a single dose of 5-FU (165 mg/kg, i.p.) was characterized by increased apoptosis, decreased necrotic fraction, and tumor shrinkage within 48 h. No significant change in normalized trimethylamine and lactate levels was observed during 3 days of untreated tumor growth. Following treatment with 5-FU, normalized intensities of both trimethylamine and lactate decreased significantly from pretreatment levels within 24 h and continued to decline at 48 h. The decrease in lactate levels determined by spectroscopic imaging in vivo was also observed in per...
In vivo nuclear magnetic resonance (NMR) spectroscopy is a rapidly developing, noninvasive analyt... more In vivo nuclear magnetic resonance (NMR) spectroscopy is a rapidly developing, noninvasive analytical technique that allows sequential studies of brain tumor metabolism. It can be implemented on most conventional high-field magnetic resonance imaging scanners. In animal tumor models, NMR spectroscopy has been used extensively to characterize the metabolic changes associated with tumor growth and response to therapy. Preliminary data in humans indicate the feasibility of recording phosphorus and proton spectra from focal lesions within the brain. It is hoped that the technique will provide useful prognostic information in terms of tumor growth behavior and prediction and detection of response to therapy. However, the technique suffers from relatively coarse spatial resolution, and the methodology is still under development. More studies with larger patient groups are required before the clinical utility of the technique can be fully evaluated.
A novel single-scan selective homonuclear multiple-quantum coherence-transfer technique, Sel-MQC,... more A novel single-scan selective homonuclear multiple-quantum coherence-transfer technique, Sel-MQC, is presented that achieves lactate editing with complete lipid and water suppression. The method is suitable for studying tissues with high fat content and those subject to substantial motion. Frequency-selective excitation is employed to selectively prepare lactate into its multiple-quantum states; lipid and water are left in the single-quantum modes and eliminated by the multiple-quantum selection gradients. The efficiency of lipid suppression is monitored by a 2D Sel-MQC experiment which separates lipid and lactate along the multiple-quantum-evolution dimension. The spatial distribution of lactate can be imaged by the spectroscopic imaging version of Sel-MQC. Sel-MQC sequences were demonstrated both in phantoms and in vivo, using subcutaneously implanted murine EMT6 tumors.
We have used in vivo 31P-nuclear magnetic resonance spectroscopy to study the changes in high-ene... more We have used in vivo 31P-nuclear magnetic resonance spectroscopy to study the changes in high-energy phosphates following hyperthermia. Immediately after heating, there is a fall in adenosine triphosphate and apparent intracellular pH and an increase in inorganic phosphate. Following sublethal heating (40 degrees for 15 min), these changes were partial, and they resolved over the subsequent 45 hr. With tumors given severe hyperthermia (47 degrees for 15 min), there was complete disappearance of adenosine triphosphate, with no recovery by 24 hr posttreatment. Qualitatively similar effects were seen after heating of normal leg muscle. The degree of fall of the adenosine triphosphate/inorganic phosphate concentration ratio was directly proportional to the heat dose and to thermal cell kill. 31P-Nuclear magnetic resonance spectroscopy may be useful in thermal dosimetry and treatment evaluation following hyperthermia.
If tumor volumes are to be used for evaluating responses to treatment and long-term outcomes of p... more If tumor volumes are to be used for evaluating responses to treatment and long-term outcomes of patients with primary pharyngeal carcinomas, the reproducibility of these measurements must be established. We determined the intraobserver variability of MR imaging-based volume measurements of these cancers and their regional metastases. We used an interactive computer program (IDL) that enables the extraction of tumor volumes from 3D MR data to obtain 202 volume measurements in 17 patients with pharyngeal carcinoma (two to five time points each). The primary cancer and largest nodal mass were manually outlined on every T2-weighted image of each MR study. The same neuroradiologist reanalyzed this MR dataset 2-41 weeks later. Measurement error and percentage measurement error (intraobserver variability) were determined. Differences in intraobserver variability between primary lesions and nodes, as well as between stages of treatment were tested with a Wilcoxon rank sum test. The mean and...
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